Successful clinical strategies to establish stable mixed hematopoietic chimerism in patients with hemoglobinopathies using non-toxic myelopreparative regimens could cure a large number of patients for whom the toxicity of bone marrow transplantation is prohibitive. A promising non-myeloablative approach that can consistently achieve mixed allochimerism is in utero hematopoietic stem cell transplantation (IUHSCTx). Strategies for the clinical application of IUHSCTx to the hemoglobinopathies include: 1) reconstitution by IUHSCTx to achieve adequate levels of donor allochimerism for therapeutic effect; and 2) prenatal specific tolerance induction with subsequent postnatal enhancement of engraftment using minimal myeloablative regimens. The overall goal of this proposal is to investigate prenatal strategies for the treatment of the hemoglobinopathies. The specific aims of the proposal are: 1) To compare the potential of IUHSCTx to establish mixed allochimerism in the biologic milieu of different types and severity of hemoglobinopathy, using transgenic murine models of hemoglobinopathy. The efficacy of IUHSCTx will be assessed in transgenic murine models of different types and severity of hemoglobinopathy; 2) To contrast and compare the ability of HSC containing populations versus professional antigen presenting cells (APCs) to facilitate deletional tolerance after in utero transplantation. Populations of donor-derived APCs will be assessed for their ability to migrate to the recipient thymus, present donor specific antigen, and mediate clonal deletion of appropriate alloreactive T-cells; and 3) To test the efficacy of postnatal re-transplantation strategies with or without minimal myelopreparative regimens to augment engraftment after birth following the prenatal establishment of mixed allochimerism and/or donor specific tolerance. The efficacy of same donor transplants after birth to augment engraftment will be assessed in defined model systems that allow analysis of: a) the importance of achieving central deletional tolerance; b) the impact of minimal myelopreparative regimens; and c) the presence of hemoglobinopathy; on the success of this approach.